The present invention relates to a process for the preparation of 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-alpha,alpha-dimethylbenzeneacetic acid, of formula (7): 
A number of processes for the preparation of Fexofenadine (W093/21156, W097/22344 W097/23213) are known. All said processes are characterized by a high number of steps. None of the known processes envisages a convergent approach, on the contrary the final molecule is obtained through the stepwise introduction of the various functions, starting from xcex1,xcex1-dimethylbenzeneacetic acid.
A process is also known (J. Org. Chem. 1994, 59, 2620-2622) which is shown in the following scheme 1: 
This process suffers from some disadvantages which prevent its industrial application: the oxidation of the triple bond to ketone involves the use of mercuric o mercurous oxide under strongly acidic conditions, which give raise to dehydration by-products, whose formulae are reported in the following, said by-products being difficult to remove from the final product. 
An advantageous process for the preparation of Fexofenadine has now been found, as reported in the following scheme 2: 
The process of the invention comprises reacting a compound (1) wherein R1 is halogen (chlorine, bromine, iodine) or an alkyl or arylsulfonate group (methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and the like) with the compound of formula (2), to give the compound (3).
The reaction is carried out in protic solvents such as water, methanol, ethanol, isopropanol; aprotic dipolar solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide; ethers such as tetrahydrofuran, dibutyl ether, dioxane; esters such as ethyl acetate, butyl acetate; aromatic solvents such as toluene, xylene, benzene; chlorinated solvents such as methylene chloride, chloroform, carbon tetrachloride or mixtures thereof in the presence of an inorganic (carbonates, bicarbonates, alkali or alkaline-earth hydroxides) or organic base (triethylamine, diisopropylethylamine, azacyclonol, and the like) at temperatures ranging from 20xc2x0 C. to the reflux temperature of the solvent.
Compound (3), which is novel and is a further object of the invention, is then condensed with compound (4) in which R2 is hydrogen o C1-C4 alkyl, and R3 is halogen (chlorine, bromine, iodine) o an alkyl or arylsulfonate (methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl and the like) in the presence of metal catalysts based on copper(I) or mixtures of palladium(0) and copper(I), in the presence of a base.
The Cu(I) catalyst can consist of copper salts having oxidation state 1, such as cuprous oxide, cuprous chloride, cuprous bromide, cuprous iodide, cuprous acetate, and the like.
The Pd(0) catalyst comprises palladium having oxidation state 0, elemental palladium (metal, cluster, and the like), supported palladium (for example on carbon), palladium complexed with suitable ligands, or palladium generated in situ by reduction of Pd(II) salts, such as palladium acetate, palladium chloride, and the like. Suitable ligands are, for example, phosphorous (III) or nitrogen derivatives. Examples of palladium complexes comprise:
bis-(triphenylphosphine)-dichloro complex
bis-(tributylphosphine)-dichloro complex
di-allyltriphenylphosphine-dichloro complex
tetrakis-(triphenylphosphine) complex
triphenylphosphine-piperidine-dichloro complex
bis-(triphenylphosphine)-diacetate complex
2,4-pentanedione complex
1,2-bis-(diphenylphosphine)-ethane complex
bis-benzonitrile-dichloro complex.
The reaction is preferably carried out in the simultaneous presence of Pd(0), a phosphine ligand and Cu(I) salts, preferably in 1:4:2 Pd:ligand:Cu molar ratios. The palladium molar amount usually ranges from 0.01 to 0.1 relative to compound (3).
Alternatively, the reaction can be carried out in the presence of a Cu(I) salt and of a phosphine ligand in 1:2 Cu:ligand molar ratios. The copper molar amount usually ranges from 0.01 to 0.3 relative to compound (3).
The reaction is optionally carried out in the presence of a solvent selected from water-miscible alcohols, such as methanol, ethanol, isopropanol, 2-methoxy-1-propanol, N,N-dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof with water, in amounts ranging from 1 to 5 volumes relative to compound (3) at a temperature ranging from 20 to 150xc2x0 C., preferably from 60 to 120xc2x0 C.
Suitable bases are amino organic bases such as pyridine, piperidine, piperazine, morpholine, diisopropylethylamine, triethylamine, n-octylamine, and the like, preferably triethylamine or inorganic bases such as carbonates, bicarbonates, alkali or alkaline-earth oxides.
A further object of the present invention is the transformation of compound (5) into the corresponding compound (6), which is a precursor of Fexofenadine (7) (scheme 3), with a method which solves the problems described in J. Org. Chem. 1994, 59, 2620 -2622, namely the formation of dehydration products due to the strongly acidic conditions.
The transformation of compound (5) into compound (6) is carried out under neutral conditions in the presence of a catalyst based on palladium(II), platinum(II), ruthenium(III), optionally in the presence of ligands, or in the complexed form. Suitable ligands are phosphorous(III) derivatives, such as triphenylphosphine; nitrogen derivatives, such as benzonitrile, acetonitrile, EDTA or carbonyl derivatives such as carbon oxide, and the like.
The reaction is carried out in the presence of molar amounts of catalyst ranging from 0.005 to 0.1 relative to compound (5), preferably from 0.01 to 0.05.
The reaction is carried out in the presence of a water-miscible solvent, such as methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, dimethylsulfoxide in amounts ranging from 1 to 5 volumes relative to compound (5), at a temperature ranging from 20 to 150xc2x0 C., preferably from 60 to 120xc2x0 C.
Compound (6) is subsequently transformed into Fexofenadine by hydrolysis of the ester and reduction with sodium borohydride, according to conventional conditions described in literature. 
The following examples illustrate the invention in greater detail.